Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.
Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.
Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A.sub.2 synthetase inhibitors or receptor antagonists, which act against thromboxane A.sub.2 ; and hirudin, which acts against thrombin.
Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. Cell (1991) 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.
GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.
In addition to GPIIb/IIIa, increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands or other cell adhesion ligands thereby mediating cell--cell and cell-matrix adhesion processes. These receptors belong to a gene superfamily called integrins and are composed of heterodimeric transmembrane glycoproteins containing .alpha.- and .beta.-subunits. Integrin subfamilies contain a common .beta.-subunit combined with different .alpha.-subunits to form adhesion receptors with unique specificity. The genes for eight distinct .beta.-subunits have been cloned and sequenced to date.
Two members of the .beta.1 subfamily, .alpha.4/.beta.1 and .alpha.5/.beta.1 have been implicated in various inflammatory processes. Antibodies to .alpha.4 prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther-Janssen et al., J. Immunol., 1991, 147:4207). Additional studies with monoclonal anti-.alpha.4 antibodies provide evidence that .alpha.4/.beta.1 may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh et al., J. Immunol., 1991, 146:3419; Bochner et al., J. Exp. Med., 1991 173:1553; Yednock et al., Nature, 1992, 356:63). Anti-.alpha.4 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).
The .alpha..sub.v /.beta..sub.3 heterodimer, commonly referred to as the vitronectin receptor, is another member of the .beta..sub.3 integrin subfamily and has been described in platelets, endothelial cells, melanoma, smooth muscle cells and on the surface of osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826; Horton, Int. J. Exp. Pathol., 1990, 71:741-759). Like GPIIb/IIIa, the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombospondin in a manner mediated by the RGD sequence. Possible roles for .alpha..sub.v /.beta..sub.3 in angiogenesis, tumor progression, and neovascularization have been proposed (Brooks et al., Science, 1994, 264:569-571). A key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. Studies with monoclonal antibodies have implicated the .alpha..sub.v /.beta..sub.3 receptor in this process and suggest that a selective .alpha..sub.v /.beta..sub.3 antagonist would have utility in blocking bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).
Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi.
European Patent Application Publication Number 478363 relates to compounds having the general formula: ##STR1##
European Patent Application Publication Number 478328 relates to compounds having the general formula: ##STR2##
European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula: ##STR3##
PCT Patent Application 9307867 relates to compounds having the general formula: ##STR4##
European Patent Application Publication Number 4512831 relates to compounds having the general formula: ##STR5##
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
Most peptides and peptidomimetics exhibit very low oral bioavailability due to poor absorption and/or degradation in the GI tract and liver. Therefore, their use is limited to the parenteral route of administration.
Drugs with low bioavailability often have a large variability in pharmacological response due to an associated variability in drug delivery. This large variability in drug delivery may occur when the bioavailability is low because under those conditions, it takes only a small variation in bioavailability to give a large change in plasma drug concentration (W. K. Sietsema, The Absolute Oral Bioavailability of Selected Drug, International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 27 No. 4-1989 (179-211)).
Peptides and peptidomimetics have also generally shown relatively low nasal bioavailability. For example, studies with the luteinizing hormone releasing hormone (LHRH) analog, nafarelin acetate, showed that nasal bioavailability was only .about.2% (S. T. Anik, G. McRae, C. Nerenberg, A. Worden, J. Foreman, J. Hwang, S. Kushinsky, R. E. Jones, and B. Vickery; J. Pharm., Sci. 73: 684-685 (1984)). Thus, the intranasal administration of peptides and peptidomimetics is generally not recommended.